CMT1A is the most common subtype of CMT. It is caused by a duplication of the PMP22 gene. Most people have two copies of PMP22, but individuals with CMT1A have three. This extra copy disrupts how Schwann cells form and maintain peripheral nerve myelin, leading to slowed nerve signal transmission.
CMT1A is autosomal dominant, meaning that just one of the gene’s two copies needs a mutation. In the case of 1A, the mutation happens to be a third copy.
CMT1A was the first CMT subtype to have its genetic cause identified. In 1991, researchers discovered that a small segment of chromosome 17 (17p11.2–p12) was duplicated in multiple family members with CMT. Family members without CMT did not have this duplication, demonstrating that the mutation segregated with the disease.
In 1992, researchers further narrowed the cause to the PMP22 gene within this duplicated region, establishing the genetic basis of CMT1A.
Clinical Features
Symptoms often begin in childhood or adolescence, although changes in the peripheral nerves can be detected earlier through nerve conduction studies, sometimes before symptoms are noticeable. Nerve conduction in CMT1A is uniformly slowed nerve velocities, with each nerve having very similar conduction results.
CMT1A symptoms may include:
- Weakness in the feet and lower legs
- Muscle atrophy
- Foot drop
- A steppage-style walking pattern
- Foot deformities, including high arches and hammertoes (clawed toes)
- Reduced sensation
- Muscle cramping
- Reduced or absent reflexes
- Enlarged peripheral nerves (hypertrophic nerves)
- Clawing of the fingers
- Spinal curvature, including scoliosis or kyphoscoliosis
- Additional symptoms not listed here
Disease Course
CMT1A shows wide variability in severity and progression. Some individuals remain mildly affected, while others are more severely affected. Even within the same family, disease progression and severity can differ substantially. Progression is generally slow, and life expectancy is not reduced.
